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Misfolding promotes the ubiquitination of polyglutamine-expanded ataxin-3, the defective gene product in SCA3/MJD

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Abstract

A major hallmark of the polyglutamine diseases is the formation of neuronal intranuclear inclusions (NIIs) of the disease proteins that are ubiquitinated and often associated with various chaperones and proteasome components. Recently, misfolding has come to be considered one of the primary factors for polyglutamine protein aggregation, although, the nature of misfolding and the relationship between misfolding and ubiquitination of the expanded polyglutamine protein is not yet known. By using ataxin-3, the defective gene product of SCA3/MJD, we demonstrate here that the misfolding propensity and the cellular toxicity of a polyglutamine protein is directly proportional to the length of the glutamine repeats and inversely dependent on the size of the corresponding protein. The size of the polyglutamine bearing protein also inversely influences the binding of 1C2 antibody (an antibody that selectively recognizes polyglutamine expansion) to the polyglutamine protein and determines the minimum length of glutamine expansion to be recognized by 1C2 antibody, which suggests that the critical pathological range of glutamine repeats could also be dependent on the size of the corresponding protein. Ataxin-3 (both full length and truncated) with normal glutamine repeats are not ubiquitinated, however, ataxin-3 with expanded polyglutamine is ubiquitinated and the ubiquitination depends on the misfolding propensity of the polyglutamine expanded ataxin-3.

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References

  • Chai Y, SL Koppenhafer, NM Bonini and HL Paulson (1999a) Analysis of the role of heat shock protein (hsp) molecular chaperones in polyglutamine disease.J. Neurosci. 19, 10338–10347.

    PubMed  CAS  Google Scholar 

  • Chai Y, SL Koppenhafer, SJ Shoesmith, MK Perez and HL Paulson (1999b) Evidence for proteasome involvement in polyglutamine disease: localization to nuclear inclusions in SCA3/MJD and suppression of polyglutamine aggregationin vitro.Hum. Mol. Genet. 8, 673–682.

    Article  PubMed  CAS  Google Scholar 

  • Cummings CJ and HY Zoghbi (2000) Fourteen and counting: unraveling trinucleotide repeat diseases.Hum. Mol. Genet. 9, 909–916.

    Article  PubMed  CAS  Google Scholar 

  • Cummings CJ, MA Mancini, B Antalffy, DB DeFranco, HT Orr and HY Zoghbi (1998) Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1.Nature Genet. 19, 148–154.

    Article  PubMed  CAS  Google Scholar 

  • Cummings CJ, E Reinstein, Y Sun, B Antalffy, Y-H Jiang, A Ciechanover, HT Orr, AL Beaudet and H Zoghbi (1999) Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice.Neuron 24, 879–892.

    Article  PubMed  CAS  Google Scholar 

  • DiFiglia M, E Sapp, KO Chase, SW Davies, GP Bates, JP Vonsattel and N Aronin (1997) Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain.Science 277, 1990–1993.

    Article  PubMed  CAS  Google Scholar 

  • Ellerby LM, RL Andrusiak, CL Wellington, AS Hackam, SS Propp, JD Wood, AH Sharp, RL Margolis, CA Ross, GS Salvesen, MR Hayden and DE Bredesen (1999a) Cleavage of atrophin-1 at caspase site aspartic acid 109 modulates cytotoxicity.J. Biol. Chem. 274, 8730–8736.

    Article  PubMed  CAS  Google Scholar 

  • Ellerby LM, AS Hackam, SS Propp, HM Ellerby, S Rabizadeh, NR Cashman, M A Trifiro, L Pinsky, CL Wellington, GS Salvesen, MR Hayden and DE Bredesen (1999b) Kennedy’s disease: caspase cleavage of the androgen receptor is a crucial event in cyto toxicity.J. Neurochem. 72, 185–195.

    Article  PubMed  CAS  Google Scholar 

  • Ferrigno P and PA Silver (2000) Polyglutamine expansions: proteolysis, chaperones, and the dangers of promiscuity.Neuron 26, 9–12.

    Article  PubMed  CAS  Google Scholar 

  • Goldberg YP, DW Nicholson, MA Rasper, MA Kalchman, HB Koide, RK Graham, M Bromm, P Kazemi-Esfarjani, NA Thornberry, JP Vaillancourt and MR Hayden (1996) Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract.Nature Genet. 13, 442–449.

    Article  PubMed  CAS  Google Scholar 

  • Hayashi M, K. Kobayashi and H. Furata (2003) Immunohistochemical study of neural intranuclear and cytoplasmic inclusions in Machando-Joshep disease.Phychiatry Clin. Neurosci. 57, 205–213.

    Article  Google Scholar 

  • Heiser V, E Scherzinger, A Boeddrich, E Nordhoff, R Lurz, N Schugardt, H Lehrach and EE Wanker (2000) Inhibition of huntingtin fibrillogenesis by specific antibodies and small molecules: implications for Huntington’s disease therapy.Proc. Natl. Acad. Sci. USA 97, 6739–6744.

    Article  PubMed  CAS  Google Scholar 

  • Huynh DP, K Figueroa, N Hoang and S-M Pulst (2000) Nuclear localization or inclusion body formation of ataxin-2 are not necessary for SCA2 pathogenesis in mouse or human.Nature Genet. 26, 44–50.

    Article  PubMed  CAS  Google Scholar 

  • Jana NR, M Tanaka, G Wang and N Nukina (2000) Polyglutamine length-dependent interaction of Hsp70 and Hsp40 family chaperones with truncated N-terminal huntingtin: their role in suppression of aggregation and cellular toxicity.Hum. Mol. Genet. 9, 2009–2018.

    Article  PubMed  CAS  Google Scholar 

  • Jana NR, EA Zemskov, G Wang and N Nukina (2001) Altered proteasomal function due to the expression of polyglutamine expanded truncated huntingtin induces apoptosis by caspase activation through mitochondrial cytochrome c release.Hum. Mol. Genet. 10, 1049–1059.

    Article  PubMed  CAS  Google Scholar 

  • Kahlem P, C Terre, H Green and P Djian (1996) Peptides containing glutamine repeats as substrates for transglutaminase-catalyzed cross-linking: relevance to diseases of the nervous system.Proc. Natl. Acad. Sci. USA 93, 14580–14585.

    Article  PubMed  CAS  Google Scholar 

  • Kawaguchi Y, T Okamoto, M Taniwaki, M Aizawa, M Inoue, S Katayama, H Kawakami, S Makamura, M Nishimuraet al. (1994) CAG expansion in a novel gene for Machando-Joshep disease at chromosome 14q32.1.Nature Genet. 8, 221–228.

    Article  PubMed  CAS  Google Scholar 

  • Kim TW and RE Tanzi (1998) Neuronal intranuclear inclusions in polyglutamine diseases: nuclear weapons or nuclear fallout?Neuron 21, 657–659.

    Article  PubMed  CAS  Google Scholar 

  • Li X-J, S-H Li, AH Sharp, FC Nucifora, G Schilling, A Lanahan, P Worley, SH Snyder and CA Ross (1995) A huntingtin associated protein enriched in brain with implications for pathology.Nature 378, 398–402.

    Article  PubMed  CAS  Google Scholar 

  • Lin X, CJ Cummings and HY Zoghbi (1999) Expanding our understanding of polyglutamine diseases through mouse models.Neuron 24, 499–502.

    Article  PubMed  CAS  Google Scholar 

  • Mende-Mueller LM, T Toneff, S-R Hwang, M-F Chesselet and VYH Hook (2001) Tissue-specific proteolysis of huntingtin (htt) in the human brain: evidence of enhanced levels of N- and C-terminal htt fragments in Huntington’s disease striatum.J. Neurosci. 21, 1830–1837.

    PubMed  CAS  Google Scholar 

  • Paulson HL (1999) Protein fate in neurodegenerative proteinopathies: polyglutamine diseases join the misfold.Am. J. Hum. Genet. 64, 339–345.

    Article  PubMed  CAS  Google Scholar 

  • Paulson HL and KH Fischbeck (1996) Trinucleotide repeats in neurogenetic disorders.Ann. Rev. Neurosci. 19, 79–107.

    Article  PubMed  CAS  Google Scholar 

  • Paulson HL, SS Das, PB Crino, MK Perez, SC Patel, D Gotsdiner, KH Fischbeck and RN Pittman (1997) Machando-Joshep disease gene product is a cytoplasmic protein widely expressed in brain.Ann. Neurol. 41, 453–462.

    Article  PubMed  CAS  Google Scholar 

  • Perez MK, HL Paulson and RN Pittman (1999) Ataxin-3 with an altered conformation that exposes the polyglutamine domain is associated with the nuclear matrix.Hum. Mol. Genet. 8, 2377–2385.

    Article  PubMed  CAS  Google Scholar 

  • Perutz MF, T Johnson, M Suzuki and JT Finch (1994) Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases.Proc. Natl. Acad. Sci. USA 91, 5355–5358.

    Article  PubMed  CAS  Google Scholar 

  • Reddy PS and DE Housman (1997) The complex pathology of trinucleotide repeats.Curr. Opin. Cell. Biol. 9, 364–372.

    Article  PubMed  CAS  Google Scholar 

  • Rosenberg RN (1992) Machando-Joshep disease: an autosomal dominant motor system degeneration.Mov. Disord. 7, 193–203.

    Article  PubMed  CAS  Google Scholar 

  • Ross CA. (1997) Intranuclear neuronal inclusions: a common pathogenic mechanism of glutamine-repeat neurodegenerative diseases?Neuron 19, 1147–1150.

    Article  PubMed  CAS  Google Scholar 

  • Saudou F, S Finkbeiner, D Devys and ME Greenberg (1998) Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions.Cell 95, 55–66.

    Article  PubMed  CAS  Google Scholar 

  • Sherman MY and AL Goldberg (2001) Cellular defenses against unfolded proteins: a cell biologist thinks about neurodegenerative diseases.Neuron 29, 15–32.

    Article  PubMed  CAS  Google Scholar 

  • Sittler A, S Walter, N Wedemeyer, R Hasenbank, E Scherzinger, H Eickhoff, GP Bates, H Lehrach and EE Wanker (1998) SH3GL3 associates with the huntingtin exon-1 protein and promotes the formation of polygln-containing protein aggregates.Mol. Cell 2, 427–436.

    Article  PubMed  CAS  Google Scholar 

  • Stenoien DL, CJ Cummings, HP Adams, MG Mancini, K Patel, GN DeMartino, M Marcelli, NL Weigel and MA Mancini (1999) Polyglutamine-expanded androgen receptors form aggregates that sequester heat shock proteins, proteasome components and SRC-1, and are suppressed by the HDJ-2 chaperone.Hum. Mol. Genet. 8, 731–741.

    Article  PubMed  CAS  Google Scholar 

  • Stott K, JM Blackburn, PJG Butler and M Perutz (1995) Incorporation of glutamine repeats makes protein oligomerize: implications for neurodegenerative diseases.Proc. Natl. Acad. Sci. USA 92, 6509–6513.

    Article  PubMed  CAS  Google Scholar 

  • Tait D, M Riccio, A Sittler, E Scherzinger, S Santi, A Ognibene, NM Maraldi, H Lehrach and EE Wanker (1998) Ataxin-3 is transported into the nucleus and associates with the nuclear matrix.Hum. Mol. Genet. 7, 991–997.

    Article  PubMed  CAS  Google Scholar 

  • Trottier Y, Y Lutz, G Stevanin, G Imbert, D Devys, G Cancel, F Saudou, C Weber, G David, L Tora, Y Agid, A Brice and J-L Mandel (1995) Polyglutamine expansion as a pathological epitope in Huntington’s disease and four dominant cerebellar ataxias.Nature 378, 403–405.

    Article  PubMed  CAS  Google Scholar 

  • Wang G, K Ide, N Nukina, J Goto, Y Ichikawa, K Uchida, T Sakamoto and I Kanazawa (1997) Machando-Joseph disease gene product identified in lymphocytes and brain.Biochem. Biophys. Res. Commun. 233, 476–479.

    Article  PubMed  CAS  Google Scholar 

  • Wang GH, K Mitsui, S Kotliarova, A Yamashita, Y Nagao, S Tokuhiro, T Iwatsubo, I Kanazawa and N Nukina (1999) Caspase activation during apoptotic cell death induced by expanded polyglutamine in N2a cells.NeuroReport 10, 2435–2438.

    Article  PubMed  CAS  Google Scholar 

  • Wang GH, N Sawai, S Kotliarova, I Kanazawa and N Nukina (2000) Ataxin-3, the MJD1 gene product, interacts with the two human homologs of yeast DNA repair protein RAD23, HHR23A and HHR23B.Hum. Mol. Genet. 9, 1795–1803.

    Article  PubMed  CAS  Google Scholar 

  • Warrick JM, HYE Chan, GL Gray-Board, Y Chai, HL Paulson and NM Bonini (1999) Suppression of polyglutamine-mediated neurodegeneration in drosophila by the molecular chaperone Hsp70.Nature Genet. 23, 425–428.

    Article  PubMed  CAS  Google Scholar 

  • Wellington CL, LM Ellerby, AS Hackam, RL Margolis, MA Trifiro R Singaraja, K McCutcheon, GS Salvesen, SS Propp, M Bromm, KJ Rowland, T Zhang, D Rasper, S Roy, N Thornberry, L Pinsky, A Kakizuka, CA Ross, DW Nicholson, DE Bredesen and MR Hayden (1998) Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract.J. Biol. Chem. 273, 9158–9167.

    Article  PubMed  CAS  Google Scholar 

  • Wellington CL, R Singaraja, L Ellerby, J Savill, S Roy, B Leavitt, E Cattaneo, A Hackam, A Sharp, N Thornberry, DW Nicholson, DE Bredesen and MR Hayden (2000) Inhibiting caspase cleavage of huntingtin reduces toxicity and aggregate formation in neuronal and nonneuronal cells.J. Biol Chem. 275, 19831–19838.

    Article  PubMed  CAS  Google Scholar 

  • Zoghbi HY and HT Orr (2000) Glutamine repeats and neurodegeneration.Ann. Rev. Neurosci. 23, 217–247.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Cellular and Molecular Neuroscience Laboratory, National Brain Research Centre, 122 050, Manesar, Gurgaon, India

    Nihar Ranjan Jana

  2. Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, 2-1 Hirosawa, 351-0198, Wako-shi, Saitama, Japan

    Nobuyuki Nukina

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  1. Nihar Ranjan Jana
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  2. Nobuyuki Nukina
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Correspondence to Nihar Ranjan Jana.

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Jana, N.R., Nukina, N. Misfolding promotes the ubiquitination of polyglutamine-expanded ataxin-3, the defective gene product in SCA3/MJD. neurotox res 6, 523–533 (2004). https://doi.org/10.1007/BF03033448

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  • DOI: https://doi.org/10.1007/BF03033448

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